Seizure and Status Epilepticus Therapeutics: A 2005 Update

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Seizure and Status Epilepticus Therapeutics A
2005 Update
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Andy S. Jagoda, MD
Professor and Vice ChairResidency Program
DirectorDepartment of Emergency MedicineMount
Sinai School of MedicineNew York, NY
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Learning Objectives

• Review the available therapeutics available for
  seizure management in the emergency department
• Discuss the 2004 ACEP Clinical Policy as it
  pertains to therapeutics
• Identify the role for second generation
  anti-epileptic drugs in the management of
  seizures in the emergency department

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Seizure Epidemiology in Emergency Medicine

• 1 of adult ED visits
• 2 of pediatric ED visits
• Most common ED etiologies are not epilepsy
  related
• Alcoholism
• Stroke
• Trauma
• CNS infection
• Metabolic / Toxin
• Tumor
• Fever in children
• 50,000 100,000 ED cases of status epilepticus
  annually
• 20 mortality

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Seizure Therapeutics

• Old generation AEDs
• IV / PO Benzodiazepine, phenytoin,
  barbiturates, valproic acid
• PO Carbamazepine, ethosuximide
• New formulations of old generation AEDs
• Fosphenytoin, valproic acid, rectal diazepam
• Other CNS depressants
• Propofol, edomidate

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Seizure Therapeutics

• New generation
• IV / PO Levetiracetam
• PO Felbamate, gabapentin, lamotrigine,
  topiramate, tiagabine, oxcarbazepine, zonisamide,
  pregabalin

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Mechanism of Action of AEDs

• Sodium channel blockade
• Phenytoins, Carbamazepine, valproic acid,
  felbamate, lamotrigine, topiramate,
  oxcarbazepine, zonisamide
• Calcium channel blockade
• Valproic acid, lamotrigine, topiramate,
  oxcarbazepine, zonisamide, levetiracetam
• Glutamate antagonism
• Diazepam, gabapentin, topiramate
• GABA potentiation
• Diazepam, phenobarbital, valproic acide,
  felbamate, topiramate, tiagabine, zonisamide
• Carbonic anhydrase inhibition
• Topiramate, carbonic anhydrase inhibition
• Voltage sensitive calcium channel
• Gabapentin, pregabalin

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Old vs New AEDs

• Efficacy is the same old vs new AED
• 40 - 60 of patients started on an AED will
  remain seizure free at one year
• Unethical to do a placebo controlled study with a
  new AED
• In general, the new AEDs are not FDA approved for
  monotherapy

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Old vs New AEDs

• New AEDs have fewer side effects
• Exceptions felbamate and lamotrigine
• Gabapentin and levetiracetam have no protein
  binding, are renally excreted, and have no
  serious side effects reported
• Drug levels are not readily available for the new
  AEDs
• Wide safe therapeutic range
• Relatively safe in overdose

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Considerations in Choosing an AED

• Effectiveness for type of seizure
• Delivery PO, IM, PR, IV
• Onset of action
• Protein binding / competition with other drugs
• Metabolism Hepatic vs renal
• Duration of action
• Side effects hypotension, respiratory
  depression, dysrhythmias, sclerosis / necrosis

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ACEP Clinical Policy Therapeutics

• Which new onset seizure patients who have
  returned to normal baseline need to be admitted
  to the hospital and / or started on an AED?
• What are effective phenytoin dosing strategies
  for preventing sz recurrence in patients who
  present to the ED with a subtherapeutic serum
  phenytoin level?
• What agent(s) should be administered to a patient
  in status who continues to seize despite a
  loading dose of a benzodiazepine and a phenytoin?

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Question
A 25 yo man has a witnessed GC tonic clonic sz.
When he arrives in the ED, he is alert and has a
normal neurologic exam. His lab tests and CT are
normal. Which do you recommend

1. No treatment and discharge for outpatient
   evaluation
2. Load with phenytoin
3. Load with valproic acid
4. Load with a new generation AED, e.g.,
   levetiracetam or topiramate

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Treatment of First Time Seizures

• Decision to initiate AED treatment depends on the
  risk of recurrence, ie, etiology
• Etiology, CT and EEG findings are the strongest
  predictors
• Recurrence risk is up to 20 within the first 24
  hours
• 20 to 70 within 2 years
• Patients needing immediate AED treatment can be
  loaded with oral or IV phenytoin IM
  forphenytoin IV valproic acid

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Treatment of First Time Seizures

• 2004 AAN Guidelines for New Generation AEDs
• Patients with newly diagnosed epilepsy who
  require treatment can be initiaited on standard
  AEDs or on the new AEDs choice will depend on
  individual patient characteristics
• There is no significant difference in rate of
  seizure recurrence (about 50) over a one year
  period
• Decision to admit depends on assessed risk of
  recurrence, patient compliance, and patients
  social circumstances

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Question
A patient with epilepsy, on phenytoin, 300 mg qhs
is status post a typical event but back to
baseline. Serum PHT level is 6 ug/ml. Which do
you recommend?

1. Fosphenytoin, 20 PE/kg, IM in the deltoid
2. Fosphenytoin, 20 PE/kg, IV at 300 mg/min
3. Phenytoin, 20 mg/kg IV at 50 mg/min
4. Phenytoin, 20 mg/kg po and discharge after 4 hrs
5. Depends

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AED Loading

• IV phenytoin achieves therapeutic serum levels by
  the end of the infusion
• IM fosphenytoin achieves therapeutic serum levels
  within one hour post injection
• PO phenytoin, 19 mg/kg in males and 25 mg/kg in
  females single dose achieves therapeutic serum
  levels in 4 hours

Ratanakorn. J Neuro Sci 1997 14789-92 Van der
Meyden. Epilepsia 1994 35189-194
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Question
IV load with phenytoin is ordered. After 50 cc,
the nurse notes that the infusion has infiltrated
into the hand. What do you recommend?

1. Stop the infusion and administer the rest IM
2. Continue infusion but apply warm compresses to
   promote absorption
3. Inject HCO3 into the site to buffer the
   infiltration
4. Stop the IV, elevate the hand, call risk
   management

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Picture
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Picture
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Question
Patient arrives in status epilepticus. After
assessing the ABCs and checking a blood sugar,
which of the following would be your next
intervention

1. Valium 1 mg IV push q min up to 20 mg
2. Ativan 2 mg IV push q min up to 10 mg
3. Phenytoin 20 mg / kg IV over 20 min
4. Valproic acid 20 mg / kg IV over 5 min
5. Phenobarbital 20 mg / kg at 100 mg / min

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STATUS EPILEPTICUS SE Working Group(Consensus
Document)

• Management must simultaneously address
• Stabilization ABCs
• Diagnostic testing including (including rapid
  glucose)
• Pharmacologic interventions
• Drug therapy
• Lorazepam .1 mg/kg at 2 mg/min
• If diazepam is used, phenytoin must be started
  simulatneously
• Phenytoin 20 mg/kg at 25-50 mg/min (fosphenytoin
  20 mg/kg at 150 mg/min)
• Repeat phenytoin 5 mg/kg
• Phenobarbital 20 mg/kg at 100 mg/min
• Valproic acid 20 mg/kg

Epilepsy Foundation of America. JAMA
1993270854-859
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VA COOPERATIVE STUDY

• Prospective study 384 patients in CSE
• Four treatment regimens
• Phenytoin 18 mg/kg
• Diazepam plus phenytoin
• Phenobarbital 15 mg/kg
• Lorazepam .1 mg/kg
• No difference among the four groups in recurrance
  of seizures or mortality at 12 hours or 30 days
• Trend in favor of lorazepam easiest to use

NEJM 1998339792-798
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Refractory Status Epilepticus

• Systematic review of the literature
• 28 studies 193 patients
• 48 mortality
• Compared propofol, midazolam, and pentobarbital
• Outcome EEG burst suppression
• Pentobarbital (13mg/kg load followed by 2
  mg/kg/hr infusion) found to be more effective but
  associated with higher incidence of hypotension

Claassen. Epilepsia 2002 43146-153.
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ACEP Clinical Policy What agent(s) should be
administered in SE?

• Level C recommendations
• Administer 1 of the following agents
  intravenously high-dose phenytoin,
  phenobarbital, valproic acid, midazolam infusion,
  pentobarbital infusion, or propofol infusion.

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Decision Making in Status Epilepticus

• Medication history
• Is the patient on VA, phenytoin, or phenobarb
• Consideration of drug overdose
• Avoid phenytoin in managing seizures from drug
  overdose
• Co-morbidities hypotension, liver disease, renal
  disease, meningitis, CNS lesion
• Caution in using hepatically metabolized drugs in
  patients with liver disease
• Monitoring capablities
• Avoid pentabarbital unless prepared to carefully
  monitor and manage hypotension

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Conclusions

• Fosphenytoin has a better safety profile than
  phenytoin and can be safely given IM
• Consider IV VA in noncompliant patients on VA who
  seize, and considered in treating status
  epilepticus refractory to primary therapies.
• Most AEDs are metabolized in the liver attention
  must be given to avoid inducing drug
  interactions.

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Conclusions

• Levatiracetam and gabapentin are not protein
  bound, are renally excreted, and can be used in
  liver patients.
• Pharmacologic management of status epilepticus
  must be tailored to the clinical environment
  Time is brain and interventions should be
  prioritized to rapidly terminating neuronal
  discharges

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Questions??

• www.ferne.orgferne_at_ferne.orgAndy S. Jagoda,
  MDandy.jagoda_at_mountsinai.org

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